Imatinib Treatment Experience in a Public Health System, Minority Patient Population with Chronic Myelogenous Leukemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4576-4576
Author(s):  
Sunita Nathan ◽  
Shylendra Sreenivasappa ◽  
Luciano Fochesatto Filho ◽  
Decebal S. Griza ◽  
Tracy Smiley ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Patient Population ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Cell Transplant ◽  
Phase 2 ◽  
Minority Patient ◽  
Hematologic Response ◽  
Complete Cytogenetic Response

Abstract Introduction: Imatinib (STI571/ Gleevec) is a tyrosine kinase inhibitor that functions by blocking the binding of ATP to the bcr-abl tyrosine kinase, inhibiting its activity and preventing myeloid proliferation, a characteristic of CML. We report our experience with imatinib use in a minority patient population. Methods: Data from 67 patients (pts) with CML treated at Cook County Hospital, Chicago, Illinois over a 4 year period were collected. Demographics, presentation, dosage schedule, tolerability and response were analyzed. Continuous data were analyzed via Student’s T test and categorical data via Fisher’s Exact test. Results: 57 pts with complete data [mean age at diagnosis 42.8 yrs, range 19–72 yrs, 46 (80.7%) males and 11 (19.3%) females] were identified and analyzed as a retrospective cohort. 41 pts (71.9%) were between 30 and 60 yrs of age and 17 pts (29.8%) had ≥ 1 major comorbidity at presentation. 28 (49.1%) were African American (AA), 4 (7%) Asian, 5 (8.8%) Eastern European, 17 (29.8%) Hispanic, and 3 (5.3%) Middle Eastern. 50 pts (87.7%) were in chronic phase, 5 (8.8%) in accelerated phase, 2 (3.5%) in blast phase, 2 (3.5%) had granulocytic sarcomas and 5 pts (8.8%) had second malignancies at presentation. 54 pts (94.7%) were started on 400mg of imatinib. 19 pts (33.3%) had imatinib-related toxicities including skin rash, cytopenias and nausea. 17 pts (29.8%) were non-compliant with imatinib therapy. AA pts were as old as the non-AA pts [44.8 ± 12.6 yrs vs 40.9 ± 13.8 yrs, p 0.27]. Non-AA pts were predominantly male. Following imatinib therapy a hematologic response (HR) was noted in 45.7± 54.6 days (d) in AA vs 31.3 ± 23.9 d in non-AA (p= 0.27), a major cytogenetic response (MCR) in 351 ± 342.6 d in AA pts vs 289±132.7 d in non-AA (p=0.58) and a complete cytogenetic response in 664±265.1 d in AA vs 642±292.5 d in non-AA pts (p=0.87). 11 AA pts failed imatinib therapy vs 8 non-AA pts. These pts were then subjected to imatinib dose escalation (600mg or 800mg) with only 4 pts in the AA group attaining MCR and 1 pt in the non-AA group attaining CCR. 4 AA pts then received Dasatanib and 2 went on to Allogeneic Stem Cell Transplant (ASCT) and 3 pts in the non-AA group received Nillotinib or Dasatanib and 2 went on to ASCT. There were 3 deaths in the AA group vs 1 in the non-AA group. Conclusion: In this primarily minority-based cohort there appears to be no significant difference in the age or gender distribution of the AA or non-AA pts although there appeared to be a male preponderance amongst the non-AA pts. The ethnic background does not appear to affect the time to significant hematologic response, major cytogenetic response or complete cytogenetic response to imatinib therapy in the AA or non-AA pts. Since the number of patients is small, definitive conclusions in either cohort cannot be made. Further investigation in minority patients is warranted.

scholarly journals Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2573-2580 ◽  
Author(s):  
Jorge Cortes ◽  
Jeff H. Lipton ◽  
Delphine Rea ◽  
Raghunadharao Digumarti ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Confidence Limit ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Lower Confidence Limit ◽  
Hematologic Response ◽  
Lower Confidence ◽  
Omacetaxine Mepesuccinate ◽  
T315i Mutation

Abstract Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.

A Phase 1/2 Study of SKI-606, a Dual Inhibitor of Src and Abl Kinases, in Adult Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphocytic Leukemia (ALL) Relapsed, Refractory or Intolerant of Imatinib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 168-168 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Tim H. Brummendorf ◽  
Delong Liu ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Dual Inhibitor ◽  
Hematologic Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant ◽  
Complete Hematologic Response

Abstract SKI-606 is an orally available, dual Src/Abl kinase inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation in biochemical assays. BaF3 cell lines and primary cells from pts expressing different imatinib-resistant Bcr-Abl mutant proteins are sensitive to SKI-606 in vitro. Unlike imatinib and dasatinib, SKI-606 exhibits no significant inhibition of c-kit or PDGFR. This differential selectivity may result in clinical benefit by altering the safety profile. In the phase 1 portion of this phase 1/2 study, pts in chronic phase with imatinib relapsed or refractory disease were eligible for treatment with SKI-606 once-daily dosing. 18 pts [median age: 62 yrs (range 27 – 72); 14 male; 4 female; median CML duration: 5.8 yrs (range 0.9 – 11.1); and median time on imatinib (n=16): 3.9 yrs (range 0.8 – 6.5)] have been enrolled in the following dose cohorts (mg/day): 400 (3 pts), 500 (3 pts) and 600 (12 pts), and have been on treatment for 30 to 192 days. 17/18 pts remain on study; 1 pt discontinued with disease progression. The following SKI-606-related AEs have been reported (n=15, G1/2): diarrhea (87%), nausea (33%), vomiting (20%), abdominal pain (13%), rash (13%), asthenia (13%), and increased AST/ALT levels (7%). 2 pts treated at 600 mg experienced a G3 toxicity: rash and thrombocytopenia. 5 pts (4 pts at 600 mg and 1 pt at 500 mg) had dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT levels. No pleural effusion or pulmonary edema has been reported. Of the 7 pts who entered the study in hematologic relapse and have completed 1 month of treatment, all have achieved complete hematologic response. Of the 7 pts on treatment ≥ 12 weeks (time of first cytogenetic assessment), 3 pts have achieved complete cytogenetic response and 1 pt a minimal cytogenetic response. 6/7 pts who have achieved complete hematologic response had pre-treatment imatinib-resistant Bcr-Abl mutations: M351T; F359V; T315I; F359(V,F); and 2 pts with multiple mutations [L248(L,V) and H396(H,R); H396(H,P) and E286(E,G) and M351(T,M)]. The 3 pts with complete cytogenetic response had mutations: M351T; M244V; and H396(H,P), E286(E,G) and M351(T,M). Based on the emergence of 1 DLT of G3 rash, and additional G2 GI and dermatologic toxicities observed at 600 mg, 500 mg has been selected as the dose for the phase 2 portion of the study. Patients in all phases of CML and Ph+ ALL are now being enrolled. SKI-606 is well tolerated in pts with CML, with a primarily GI and dermatologic safety profile, and with encouraging evidence of clinical activity in imatinib-resistant patients with complete hematologic and cytogenetic responses.

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

1998 ◽  
Vol 16 (3) ◽  
pp. 882-889 ◽  
Author(s):  
S Sacchi ◽  
H M Kantarjian ◽  
T L Smith ◽  
S O'Brien ◽  
S Pierce ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Univariate Analysis ◽  
Group Analysis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Alfa ◽  
Myelogenous Leukemia ◽  
Costal Margin ◽  
Hematologic Response

PURPOSE To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.

A Pilot Study Evaluating the Safety and Efficacy of Imatinib Given Early after Transplant for High-Risk Philadelphia Chromosome-Postive Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1095-1095
Author(s):  
Paul A. Carpenter ◽  
David S. Snyder ◽  
Mary E. Flowers ◽  
Jean E. Sanders ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
Pilot Study ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Antigen Expression ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract Patients with Ph+ acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in stages other than first chronic phase (CP1) frequently have recurrent malignancy after allogeneic hematopoietic cell transplant (HCT). Imatinib given after HCT for the treatment of hematological relapse has been of limited success in Ph+ALL but may induce more durable remissions in CML. Hypothesis: We postulated that imatinib might be most effective for preventing hematological relapse after myeloablative HCT if given immediately after engraftment to patients without detectable leukemia, or with leukemia that can be detected only at the molecular level. Study design: A pilot study is ongoing to evaluate the safety and preliminary efficacy of imatinib begun early after myeloablative HCT and continued until post-transplant day 365 (D+365). Study participants became eligible to start imatinib (adults 400 mg/day, children 260 mg/m2/day) if the residual marrow leukemia burden at the time of initial engraftment (ANC&gt;500 on 2 consecutive days) did not exceed &gt;1/20 Ph+ metaphases, &gt;1% aberrant antigen expression on blasts by multidimensional flow, or presence of bcr/abl in &gt;5% interphase nuclei by FISH. The primary endpoint of safety was defined by ability to tolerate imatinib (adults ≥200 mg/day, children ≥100 mg/day) for ≥ 6 days/week until D+90. An attempt was made to administer higher daily doses of imatinib after D+90. Patient characteristics: Ten patients with Ph+ALL (8 CR1, 2 CR2) and 6 patients with CML (2 AP, 2 CP2, 2 CP3) have been enrolled; 13/16 had leukemia detected by molecular or cytogenetic methods at the time of transplant. Median age at transplant was 40 y (range 5–62 y). Stem cell sources were cord blood (n=1), marrow (n=4) or G-mobilized peripheral blood (n=11). Donors were unrelated (n=10) or related (n=6). Results: Imatinib therapy began in 15 patients at a median of 29 days (range 24–39 days) after HCT and has been administered for a median of 299 days (range, 33–380 days). The median of average daily doses during this time period was 400 mg/day (range 389 to 510 mg/day) among adults and 304 mg/m2/day for the 2 children. All patients tolerated imatinib at the intended dose intensity within the first 90 days after HCT. Toxicities (NCI CTC v3.0) possibly attributed to imatinib included grade 1–2 nausea (n=3), grade 1 edema (n=3), grade 1–2 anemia (n=2), and grade 3 neutropenia (n=2). Per protocol, one patient with neutropenia received 2 doses of G-CSF at D+75 and continued imatinib without neutropenia. The second patient was not given G-CSF and imatinib was held for 2 weeks from D+160 until the ANC was &gt;2000. All patients are surviving at a median of 333 days after HCT (range, 68–564), and 14/15 patients have no detectable bcr/abl transcripts in the blood or marrow. Seven patients (4 ALL, 3 CML) have completed imatinib therapy and survive at a median of 467 days after HCT (range, 410–564 days) and 6/7 have no detectable bcr/abl transcripts in blood or marrow. One patient (CML-CP3) with cytogenetic relapse at D+118 had a 4th remission after withdrawal of immunosuppression and continued imatinib but developed hematological relapse at D+429. Conclusions: We conclude that imatinib therapy can be safely prescribed early after myeloablative allogeneic HCT at a dose-intensity comparable to that used in general oncology. Preliminary efficacy data are encouraging and worthy of further study.

Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L’ Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 286-286 ◽  
Author(s):  
Herve Dombret ◽  
O.G. Ottmann ◽  
G. Rosti ◽  
B. Simonsson ◽  
R.A. Larson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
Hematologic Response ◽  
Grade 3 ◽  
Philadelphia Chromosome Positive

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Imatinib in Children with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP CML): AAML0123 COG Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2140-2140 ◽  
Author(s):  
Martin A. Champagne ◽  
Cecilia Fu ◽  
Myron Chang ◽  
Linda Cooley ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
White Cell Count ◽  
Phase 1 ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Minor Response ◽  
Complete Cytogenetic Response

Abstract Introduction. Our prior phase 1 study (P9973) established the safety profile and suggested efficacy of imatinib in children with CP CML at doses varying from 260–570 mg/m2. The purpose of this phase 2 study was to define the rates of response in children with previously untreated CP CML. Methods. Patients less than 22 years of age at study entry with newly diagnosed CP CML, with no prior therapy other than hydroxyurea, were eligible. Imatinib was administered orally at a dose of 340 mg/m2 daily, with courses defined as 28-day intervals. A hematological response (HR) was defined at the end of courses 1 and 2 as a reduction in the white-cell count to &lt;10 x 109/L and in platelet count to &lt;450 x 109/L, and was considered a complete response (CHR) when maintained for at least four weeks. Cytogenetic response is defined as follows, based on the absolute percent of Ph+ metaphase cells on marrow specimens: complete cytogenetic response (CCyR) 0% Ph+ cells; partial (PCyR)1–35%; minor 39–65%; minimal 66–95%; none 96–100%. Iterative cytogenetic analyses were performed every 3 months during therapy. Toxicities were reported prospectively using the NIH CTCv2.0 criteria. Results. 50 children (42% boys), with a median age of 11.8 years (range 2.3–19.1) completed more than one course of therapy and were evaluable for response. Median number of courses delivered was 22.5 (range 1–43), with a median follow-up of 795 days. 96% of the calculated dose was administered. Eleven patients experienced 14 non-hematological grade 2–4 adverse events, and one patient discontinued therapy because of toxicity. The HR and CHR rates were 78% and 12%, at the end of course 1, and 20% and 78%, respectively, at the end of course 2. Only one patient was reported as a hematologic non-responder at the end of course 2. At the end of the third course, 33 patients were evaluated for cytogenetic response. Twelve (36%) children were in CCyR; 10 (30%) in PCyR; 5 in minor response; 4 in minimal response; 2 with no cytogenetic response. Six patients did not have cytogenetic evaluation; while in 11 (33%) the study was not possible due to insufficient sampling. Overall, 33 (66%) CCyRs were documented, at a median time of 5.6 months (91% documented by 9 months). Only 1 patient achieved a CCyR after course 10. Thirty-three children were removed from protocol, of which 23 underwent stem cell transplantation. One patient progressed to blast phase while on therapy, while six additional patients had cytogenetic progression. Of the 3 remaining patients, two patients had difficulty with taking medications and one had grade 4 liver toxicity. At 1 year, the estimated event free and overall survivals are 96% and 98%, respectively. Conclusion. Imatinib is well tolerated in previously untreated children with CP CML and induces comparable rates of complete cytogenetic response to those observed in adults. Current evaluation of molecular response is being performed.

Significance of Rising Levels of Minimal Residual Disease in Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+ CML) in Complete Cytogenetic Response (CGCR)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 445-445 ◽  
Author(s):  
Hagop M Kantarjian ◽  
Jianqin Shan ◽  
Dan Jones ◽  
Susan O’Brien ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Disease Status ◽  
Myelogenous Leukemia ◽  
Therapeutic Interventions ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Cell Transplant

Abstract Background . Patients with Ph+ CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by quantitative polymerase chain reaction (QPCR) studies for minimal molecular disease. The clinical significance of rising levels of QPCR in CGCR is uncertain. Study Aims . To evaluate the relevance of increases of QPCR levels in patients with CML in CGCR on therapy. Study Group and Methods . Of 258 patients on imatinib therapy for newly diagnosed CML, 116 patients in durable CGCR on imatinib therapy for at least 18 months had significant QPCR increases (documented at least twice) as defined by literature reports. These were analyzed by the achievement of major molecular response (MMR; QPCR &lt; 0.05%), and by the degree of QPCR increase. Results. The outcome of patients by disease status (still in MMR vs. loss of MMR vs. never in MMR) and by the QPCR level increase are shown in the Table. Only 13 of 116 patients (11%) with significant QPCR increases had CML progression; 11 of them were among 44 patients (25%) who either lost a MMR or never had a MMR, and had &gt; 1 log increase of QPCR. The 5-year survival of all 116 patients was 92%, suggesting the minimal relevance of QPCR increases in patients in CGCR. Conclusion . Most patients with significant QPCR increases remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have &gt; 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions. Allogeneic stem cell transplant should not be considered in view of the excellent survival. Outcome of Patients in CGCR by QPCR Increases Disease Status QPCR Log increase No. Patients CML Progression Median follow-up from QPCR increase in months (range) Persistent MMR Any 28 0 36 (3–62) Loss of MMR &gt;0.5–1 12 0 34 (14–59) &gt;1–2 25 3 31 (6–52) &gt;2 11 4 45 (20–57) Not in MMR &lt;1 32 2 35 (10–70) &gt;1 8 4 25 (12–56)

A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph+) Leukemias Including Patients with T315I Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 601-601 ◽  
Author(s):  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
Hagop M Kantarjian ◽  
Hedy Smith ◽  
Dale Bixby ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Dose Level ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Lower Extremity Weakness ◽  
Hematologic Response ◽  
T315i Mutation ◽  
Dose Levels

Abstract Abstract 601 Background. DCC-2036 is a novel and potent tyrosine kinase inhibitor (TKI) which binds to a novel region called the switch pocket, thereby preventing BCR-ABL from adopting a conformationally active state. Efficacy against multiple imatinib-resistant BCR-ABL mutants has been demonstrated both in vitro and in vivo (Chan et al., Cancer Cell 2011;19:556). Importantly, DCC-2036 retains full potency against the T315I mutant in preclinical efficacy studies. Methods. This study was designed to find the maximal tolerated dose (MTD) of DCC-2036 when administered daily as a single-agent on a 28-day cycle. Eligible patients included adults with Ph+ CML/ALL who were refractory/intolerant to ≥2 TKI's or were T315I positive. Initially DCC-2036 capsules were administered orally once daily (QD) at increasing dose levels. Only 1 patient was enrolled in each of the lowest dose cohorts of 57mg QD and 114 mg QD. For higher doses, 3– 6 patients were enrolled into each ascending dose cohort with standard dose limiting toxicity (DLT) rules evaluating safety in cycle 1 to determine dose escalation. A transition from unformulated capsules (C) to formulated tablets (T) occurred after the 1200 mg QD dose level. Paired blood samples were obtained for PK and PD assessments. Results. 30 patients (16 males, 14 females; median age 59, range 31 – 80) with CML including 19 in Chronic (CP); 8 in Accelerated (AP) and 3 in Blast (BP) Phase were enrolled. Enrolled patients had received 1–6 prior CML treatments, and 11 patients had the T315I mutation. To date, a total of 212.5 (median 5.6; range 0.2 – 23.4) 28-day cycles were administered over 10 dose levels either as C (7 dose levels) or T (3 dose levels). The 7 C dose levels were studied first and included 57 mg QD through 1200 mg QD. Following transition to T, evaluation continued with 100 mg QD, 100 mg twice daily (BID), and 200 mg BID. Two reversible DLTs (Grade 3 peripheral neuropathy and Grade 4 lower extremity weakness) occurred during the initial treatment cycle at the 200 mg T BID dose level. Evaluation of 6 patients at the 150 mg T BID dose level determined that dose to be the MTD. Preliminary safety data show that other Grade (Gr) 3/4 adverse events (AEs) were Gr 3 slurred speech and Gr 3 eruptive nevi. Gr 1/2 AEs included dry mouth, constipation, diarrhea, paresthesias, and retinal vein occlusion. There was 1 case of Gr 2 pancreatitis that recurred on rechallenge in a patient with previous pancreatitis with nilotinib. Preliminary responses include one major molecular response in a CP patient with T315I mutation who started on capsules and transitioned to 100 mg T QD. There was one complete cytogenetic response in a CP patient at 100 mg T BID, and one partial cytogenetic response in a CP patient who started on capsules and transitioned to 100 mg T BID. One patient with AP CML and T315I mutation had a complete hematologic response at 450 mg C QD. Another patient with AP CML had a partial hematologic response after receiving 200 mg BID for 1 cycle and then downdosing to 100 mg T BID. Four out of 8 patients receiving 100 mg tablets and evaluable for efficacy (completed 3 cycles of treatment) had responses. PK results indicate dose-related, nonlinear increases in both peak plasma concentration (Cmax) and exposure (AUC). PD results reveal both acute and steady state post-treatment reductions in phospho-protein levels on Days 1 and 8. Marked reductions in pSTAT5 and pCRKL have been observed in subjects with both CP and AP and appear to be required for clinical response. Conclusion. The MTD of DCC-2036 tablets is 150 mg BID. Preliminary results suggest that DCC-2036 is well tolerated and has anti-leukemia activity in subjects with refractory CML and T315I positive disease. PD results are consistent with inhibition of BCR-ABL signaling in this first-in-man study of a switch pocket tyrosine kinase inhibitor. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Bixby:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Rafferty:Deciphera Pharmaceuticals: Employment. Berger:Deciphera Pharmaceuticals: Employment. Wise:Deciphera Pharmaceuticals LLC: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment. Smith:Deciphera Pharmaceuticals: Employment. Van Etten:Deciphera Pharmaceuticals: Consultancy, Research Funding.

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